Layer I of the cerebral cortex in the aging monkey is unique in that it shows the most marked diversity of age-related changes. With increasing age it becomes thinner, the outer band of myelinated axons in layer Ib becomes less obvious, and the glial limiting membrane becomes much thicker. In addition there are obvious degenerative alterations in the apical dendritic tufts of the pyramidal cells that largely occupy layer I, and some of the cell bodies of neurons in layer I show degenerative changes. These changes in layer I are in striking contrast to remainder of the cerebral cortex which shows evidence only of degenerating myelinated fibers. Since layer I is largely occupied by the apical tufts of pyramidal cells, these alterations in layer I must have a profound effect upon the functioning of these cells and they may be causally related to the loss of cognitive function in the aging monkey. The source of the myelinated fibers that are present in layer I is unknown. Known projections to layer I include fiber plexuses intrinsic to the cortical area, corticocortical projections from other cortical areas such as callosal and feed-back projections, and projections from subcortical nuclei. Our studies to date have shown evidence of cell loss in these subcortical nuclei, with many of them showing a significant correlation of the cell loss with deficits in cognitive function. We now propose to investigate the interrelationship between the age-related changes in layer I and its afferent connection, the relationship of these changes to declines in cognitive function, and to explore the mechanism of cell loss in the subcortical nuclei.